Chronic kidney disease (CKD) affects many patients, particularly in the aging population with significant morbidity resulting in a costly public health problem. There is increasing realization for the importance of early detection and prevention, but to date there are few effective preventive measures. We have exciting preliminary data that suggest a novel, diet-induced gut microbiota-mediated pathway may serve as direct contributor to CKD susceptibility and adverse prognosis. In the present application we will interrogate each facet of the dietary-induced gut microbial pathway at the biochemical, animal model, and human clinical level. We will examine the role of specific chronic dietary exposures in risk for adverse CKD progression. We will examine the role of gut microbes in CKD susceptibility, and specific microbial enzyme systems in this process. We also will perform large scale human clinical studies testing whether gut microbial generated products detected in the circulation predict incident risk for development and progression of CKD. Finally, we will explore the potential efficacy of novel anti-microbial targeted therapy and dietary modifications for the prevention of dietary-induced CKD. Successful completion of the proposed studies should provide both important mechanistic insights into a new pathway that contributes to CKD development, as well as develop novel diagnostic tests and therapeutic approaches for the prevention of CKD.